Using Preoperative UFT to Predict Sensitivity to Fluoropyrimidines in Colorectal Cancer

Using Preoperative UFT to Predict Sensitivity to Fluoropyrimidines in Colorectal Cancer

ABSTRACT: This study was designed to determine if
histopathologic evaluation of patients with resectable colorectal
cancer following preoperative chemotherapy with uracil and tegafur
with a molar ratio of 4:1 (UFT) could predict chemosensitivity to
postoperative fluoropyrimidines to prevent recurrence of disease. In
this prospective randomized study involving 152 colorectal cancer
patients, UFT 600 mg/day was administered for 10 days prior to
surgery. Histopathology of the resected tumor was assessed, including
the amount of necrosis or disappearance of tumor, and patients were
thereafter stratified into two groups according to tumor response to
preoperative therapygrade ³
2 (sensitive) vs those with grade £
1B (not sensitive). The patients were then randomly assigned to
postoperative adjuvant UFT (400 mg/day for 12 months) or no
treatment. At the time of this evaluation, the mean total
preoperative UFT dose per patient was 7.76 g ± 3.27 g. Thirteen
patients were considered ineligible; therefore, 139 patients were
included in the analysis. Stratification resulted in 22 (15.8%) cases
in the sensitive group, of which 13 received adjuvant chemotherapy
and nine were assigned to no treatment; 117 (84.2%) patients were
considered nonsensitive, 60 of whom received adjuvant chemotherapy,
and 57 of whom received no adjuvant therapy. Among nonsensitive
patients, 3-year survival rates were 87.6% with adjuvant chemotherapy
and 84.9% with no therapy, indicating no significant difference
between groups. Among responders, however, there was a significant
difference in 3-year survival rates: 100% for the adjuvant group and
62.5% for the no-treatment group (P = .0351). These findings suggest
that histopathologic assessment following preoperative UFT
chemotherapy provides information to predict fluoropyrimidine
sensitivity. We believe grade 1B patients (19.8%) may respond to
modulated fluorouracil. We also recommend the use of other drugs,
such as irinotecan (CPT-11 [Camptosar]) and oxaliplatin, for patients
with tumor responses of grades 0 and 1A. [ONCOLOGY 7(Suppl 3):55-60, 1999]

Introduction

Uracil and tegafur (in a molar ratio of 4:1
[UFT]) plus oral calcium folinate make up the compound known as
Orzel. Recent experience with this agent suggests a high response
rate in metastatic and advanced colorectal cancer.[1] UFT has been
commercially available in Japan since 1984 and is now widely used for
the adjuvant treatment of gastric, colorectal, and breast cancers. It
is administered as a long-term oral agent in mildly toxic, divided
daily-dose schedules.[2] Comparison of the activities of long-term
oral administration of UFT vs tegafur alone in the treatment of
patients with curatively resected colorectal cancer has been carried
out in large clinical, randomized, controlled studies in Japan.[3] In
these trials, there were no benefits to UFT therapy in 5-year
survival, except among the subgroup of patients with Dukes C
rectal carcinoma.

In our previous study, we attempted to improve survival for 185
patients with operable colorectal cancer by delivering preoperative
UFT 600 mg/day for 10 days and postoperative adjuvant UFT 400 mg/day
for 12 months.[4] Although administration of preoperative oral UFT
yielded no survival benefit, macroscopic changes were noted in
resected tissue of some treated patients (Figure
1). Histologic assessment of these tumors revealed moderate
histopathologic changes, such as necrosis, loosening of cell-to-cell
contact, and vacuolation of nuclei. On reexamination of tumor
samples, it was shown that 22.2% of 126 UFT-pretreated colorectal
cancer patients had moderate or marked tumor histology changes
(grades 2 or 3), whereas only one of 48 nontreated patients (2.1%)
showed a moderate cellular change (Table
1).

Based on these findings, we theorized that histopathologic changes
following preoperative UFT chemotherapy might predict
chemosensitivity to fluoropyrimidines. To test this hypothesis, we
designed a controlled trial specifically to assess the predictive
value of histopathologic changes associated with preoperative UFT
chemotherapy for sensitivity to postoperative adjuvant
fluoropyrimidine-based therapy in patients with resectable colorectal cancer.

Patients and Methods

Eligibility

Eligibility was based on the following characteristics: 1)
histologically proven colorectal cancer; 2) potential for complete
resection; 3) early cancer excluded; 4) < 75 years of age; and 5)
written informed consent.

Preoperative Chemotherapy

The preoperative chemotherapy regimen included oral UFT 600 mg/day
(200 mg three times daily) administered for at least 10 days prior to surgery.

Histopathologic Assessment

Resected tumors were stained by routine hematoxylin and eosin
(H&E). Histopathologic effects at the maximum section (center) of
the tumor were estimated by the amount of necrosis or total amount of
tumor disappearance. These effects were then categorized into four
categories, including two subcategories for grade 1: Grade 0
represents no change, where neither necrosis nor cellular change can
be seen throughout the lesion. Grade 1A describes necrosis or tumor
reduction in less than one third of the lesion; grade 1B represents
necrosis or tumor reduction in no more than two thirds of the lesion.
Grade 2 indicates a moderate change marked by necrosis or
disappearance of tumor in more than two thirds of the lesion, with
viable tumor cells remaining. Grade 3 describes a pathologic complete
response, leaving no observable viable tumor cells. Figure
2 illustrates (at 20 × magnification) a typical case of
grade 2 tumor changes involving necrosis or disappearance of more
than two thirds of the lesion, with viable tumor cells remaining. Figure
3 is a high-powered view of a grade 2 tumor response,
delineating vacuolation of cancer cells and loosening of cell-to-cell contact.

Randomization Procedures

Before randomization, patients were stratified according to tumor
site (ie, colon or rectum) and results of histologic grading (ie,
grade ³ 2 [sensitive group] and grade £
1B [nonsensitive group]). Patients from both the sensitive and
nonsensitive groups were then randomly assigned to either
postoperative adjuvant chemotherapy with UFT 400 mg/day (200 mg twice
daily) for 12 months, or no treatment (Figure
4).

Statistical Methods

Survival and recurrence curves were calculated using the standard
Kaplan-Meier methodology. Log-rank statistics were used to compare
survival distributions.

Results

A total of 152 patients were entered in this trial, among whom 78 had
colon cancer and 74 had rectal cancer. UFT was administered
preoperatively to a mean total dose of 7.76 g ± 3.27 g. At the
time of analysis, 13 patients (8.6%) were ineligible (five colon
cancers and eight rectal cancers), leaving 139 patients available for evaluation.

On histologic grading, 13 cases (9.4%) were grade 0, 72 cases (51.8%)
were grade 1A, 32 cases (23.0%) were grade 1B, and 22 (15.8%) were
grade 2. There were no grade 3 cases. Twenty-two (15.8%) cases were
stratified into the sensitive group and 117 (84.2%) cases were
stratified into the nonsensitive group. From the 22 sensitive cases,
13 cases were randomly assigned to adjuvant chemotherapy, and nine to
no adjuvant chemotherapy. From the 117 nonsensitive cases, 60 cases
were randomly assigned to adjuvant chemotherapy and 57 to no
treatment (Table 2). There were
no significant differences in preoperative patient characteristics or
surgical findings between the two study groups.

Toxicity

There were no toxicities or operative complications related to
preoperative chemotherapy. No severe (grades 3 or 4) toxicities
related to postoperative adjuvant chemotherapy occurred.

Patient Survival and Disease-Free Rates

Patient survival and disease-free rates are illustrated in
Figure 5 and Figure 6.
Among pretreatment nonresponders, 3-year survival rates were 87.6% in
the adjuvant-chemotherapy group and 84.9% in the no-chemotherapy
groups (no significant difference). Among responders, 3-year survival
rates were 100% in the adjuvant-chemotherapy group and 62.5% in the no-chemotherapy
group (P = .0351). Three-year disease-free survival rates among
nonresponders were 81.7% and 80.1%, with and without adjuvant
chemotherapy, respectively. For responders, the 3-year disease-free
survival rates were 100% among patients receiving adjuvant
chemotherapy and 60.0% in the no-treatment group (P = .0715).

Discussion

In Japan, UFT, either alone or in combination with mitomycin C
(Mutamycin), has been evaluated as adjuvant chemotherapy for
colorectal cancer following curative resection.[5,6] In our previous
randomized, controlled study, we tested for evidence of a survival
benefit when preoperative chemotherapy with UFT 600 mg/day for 10
days was combined with postoperative adjuvant chemotherapy (UFT 400
mg/day for 12 months).[4] Unfortunately, there was no survival
advantage associated with preoperative use of UFT: 5-year survival
rates were 76.9% among 92 patients preoperatively treated with UFT
and 82.4% in 93 patients who did not receive preoperative
chemotherapy. However, remarkable macroscopic changes were observed
in resected tissue from some patients who had received 10 days
preoperative oral UFT therapy. Histologically, these changes included
ballooning or vacuolation of cells, pyknosis of nuclei, degradation
or disorganization of glandular structures, necrosis of cells or
tissue, disappearance of cells, granuloma formation (including
histiocytic aggregation), and fibrosis with or without myxoid change.

On histopathologic reexamination, 25 of the 126 (20.0%)
UFT-pretreated patients showed evidence of moderate cellular changes
(grade 2), and three patients (2.4%) showed histopathologic complete
response (grade 3) at maximum section. In 48 patients who received no
adjuvant chemotherapy, only one patient (2.1%) exhibited grade 2
changes (estimation pathologist did not know preoperative
chemotherapy status). These findings suggest that histologic changes
during preoperative chemotherapy may serve as a chemosensitivity test
in vivo for patient response to fluoropyrimidine-based therapy.

There have been other well-known in vitro chemosensitivity tests,
such as the succinate dehydrogenase inhibition (SDI) assay,
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT)
assay, and human tumor clonogenic assay (HTCA).[7,8] These assays,
however, are complicated and have a low cost-benefit ratio.
Preoperative UFT administration, on the other hand, has low toxicity,
requires only H&E staining and histologic estimation, and is
considered a safe and cost-effective in vivo analysis.

In the present randomized, controlled study, we attempted to
determine if histologic gradings after pretreatment with UFT could
predict response to postoperative adjuvant chemotherapy. Our 3-year
disease-free and overall survival rates were 100% among patients
considered histopathologically sensitive (grade ³
2); three of the nine patients in the sensitive group who did not
receive adjuvant chemotherapy died. There was no significant
difference in disease-free and overall survival rates between
treatment groups among nonsensitive patients.

Conclusion

We conclude that histopathologic analysis to determine response to
preoperative UFT chemotherapy can predict sensitivity to
fluorouracil-based treatment, enabling directed postoperative
adjuvant chemotherapy to sensitive patients. In our present study,
grade ³ 2 sensitivity was observed in
15.8% of patientsa rate similar to the response rate observed
with conventional fluoropyrimidine or UFT treatment.[2] We believe
that grade 1B patients (23.0%) may respond to a modulated
fluoropyrimidine (Orzel), such as UFT plus oral calcium folinate.
Treatment with other drugs, such as irinotecan and oxaliplatin,
should also be considered for patients with grades 0 and 1A response
to preoperative UFT.[9,10]